Red blood cells, white blood cells, and platelets are important for the clinical diagnosis of intrinsic blood cell and hematopoietic disorders, and also as predictors of various heart, lung, and blood disease outcomes. Moreover, hematologic quantitative traits are highly heritable and serve as a model system for studying the genetic architecture of complex traits. While significant strides in understanding the genetic basis of hematological traits have been made over the past decade, the wealth of whole genome sequencing (WGS) data from emerging resources such as the NHLBI Trans-Omics for Precision Medicine (TOPMed) program provides an unprecedented opportunity to gain further insight in several key areas, including the role of structural variants (SVs). While a few common SVs (e.g., α-globin) are known to be associated with blood cell traits, a more systematic and agnostic genome-wide search for SVs in large samples is required to identify new biology. The centralized availability of deeply sequenced DNA from the NHLBI TOPMed and the NHGRI Centers for Common Disease Genomics (CCDG) programs, along with genome-wide data from UK Biobank and other cohorts, allows for full characterization of SVs genome-wide at population-scale. By improving the accuracy of genome-wide SV calling for WGS data as implemented in our new Genvisis software package and by validating candidate causal SVs using state-of-the-art gene-editing technologies in hematopoietic cells, our interdisciplinary approach will facilitate the translation of genetic association findings into mechanistic insights, discover new biology underlying hematopoiesis, and ultimately identify factors that account for individual differences in pathobiology or response to treatments. In Aim 1, using WGS data from TOPMed and CCDG participants, we will apply novel methodology to generate high-quality and more accurate SV calls than the SV calling algorithms currently available for both WGS and existing array data. In Aim 2, we will use the newly generated SV calls to conduct single-variant and gene-based segmental association analyses of SVs with blood cell traits and related clinical outcomes in up to 570,319 participants. Association findings will be replicated in up to 760,000 participants in populations/studies not used in the discovery phase. SVs that are significantly associated with blood cell traits will subsequently be tested for association with other blood disorders including clonal hematopoiesis of indeterminate potential (CHIP) and VTE. In Aim 3, targeted long-range sequencing will be performed in selected samples to precisely localize newly identified blood trait-associated SVs in complex genomic regions. We will also perform functional genomic annotation of replicated blood cell trait-SV associations followed by state-of-the art gene-editing approaches to understand novel mechanisms underlying genetic regulation of hematopoiesis. This model integrative approach to advancing precision medi...